Mutations

PSEN1 V89L (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637682 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation has been reported in two individuals. It was first identified in a patient with early onset, pathologically confirmed Alzheimer’s disease (Liu et al., 2017). Symptoms began at age 39 with memory difficulties. Neuropsychological testing at age 40 revealed deficits in memory, abstraction, and problem-solving. MRI did not show brain atrophy at this time, but FDG-PET showed hypometabolism in temporal and parietal lobes. Cognitive function continued to deteriorate, and the patient died at age 49. There was no clear family history of dementia.

In a subsequent study, the variant was described in a Hungarian woman whose symptoms began at age 52 and included short-term memory loss, anxiety, and executive dysfunction. She had a family history of dementia. 

This mutation was not found in the 1000 Genomes, Exome Variant Server, ExAC, or AD&FTD databases. A PSEN1 V89L mutation due to a different nucleotide transversion was previously identified in a Spanish family with early onset AD (Queralt et al., 2002).

Neuropathology

At autopsy, typical AD pathology was observed, along with cerebral amyloid angiopathy. Amyloid plaque pathology was assessed as Thal phase 4, and neurofibrillary tangle pathology as Braak stage VI.  Atrophy and gliosis were widespread, including neocortical areas, medial temporal structures, and thalamus. No Lewy bodies were observed.

Biological Effect

Two in-depth studies of the Aβ peptides produced by cells transfected with V89L (nucleotide change specified in only one case) revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Petit et al., 2022; Liu et al., 2022; Apr 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset.

An in vitro assay using purified proteins to test the ability of this mutant (nucleotide change unspecified) to cleave the APP-C99 substrate revealed it produces less Aβ42, and even less Aβ40, than wild-type PSEN1, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017).  

In addition, characterization of an induced pluripotent stem cell line derived from the Hungarian carrier mentioned in the previous section revealed elevated tau phosphorylation, increased Aβ40 and Aβ42 levels, and an elevated Aβ42/Aβ40 ratio (Ochalek et al., 2017). 

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. V89L (G>C): Although results from different assays were mixed, two in-depth studies probing production of multiple Aβ peptides indicated a pathogenic effect.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 27 Jun 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. . Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.
  2. . A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances. J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):266-9. PubMed.
  3. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  4. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  5. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  6. . Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther. 2017 Dec 1;9(1):90. PubMed.
  7. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Other Citations

  1. PSEN1 V89L

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.

Other mutations at this position

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